Breath of fresh air for brain 'glue' cells

A type of brain cell thought to be responsible for supporting other cells may have a previously unsuspected role in controlling
breathing.

Star-shaped cells called astrocytes, found in the brain and spinal cord, can 'sense' changes in the concentration of carbon
dioxide in the blood and stimulate neurons to regulate respiration, according to a study published online in Science today1. The research may shed some light on the role of astrocytes in certain respiratory illnesses, such as cot death, which are
not well understood.

Astrocytes are a type of glial cell — the most common type of brain cell, and far more abundant than neurons. "Historically,
glial cells were only thought to 'glue' the brain together, providing neuronal structure and nutritional support but not more,"
explains physiologist Alexander Gourine of University College London, one of the authors of the study. "This old dogma is
now changing dramatically; a few recent studies have shown that astrocytes can actually help neurons to process information."

"The most important aspect of this study is that it will significantly change ideas about how breathing is controlled," says
David Attwell, a neuroscientist at University College London, who was not involved in the study.

“What this study does is beautiful and very exciting.”

During exercise, the amount of CO2 in the blood increases, making the blood more acidic. Until now, it was thought that this pH change was 'sensed' by specialized
neurons that signal to the lungs to expel more CO2. But the study found that astrocytes can sense such a decrease in pH too — a change that causes an increase in the concentration
of calcium ions (Ca2+) in the cells and the release of the chemical messenger adenosine-5'-triphosphate (ATP). The researchers think that ATP stimulates
nearby neurons that are involved with respiration; these in turn trigger increased breathing so that excess CO2 can be removed from the blood.

One of the techniques the team used was to insert a gene encoding a calcium-sensitive fluorescent protein, Case12, into the
brains of living rats, along with a promoter sequence that ensured the gene would express only in astrocytes. When light was
shone on the brain, Case12 fluoresced with a brightness corresponding to the concentration of calcium in the astrocytes. The
team found an immediate increase in calcium when the pH level was lowered. The experiment also revealed that these astrocytes,
reacting to changes in pH, are located in the medulla oblongata — an area of the brain known to 'sense' the chemical composition
of blood. The team observed similar results using rat brainstem slices and cell-culture models.

Fast response

The researchers hope that the findings may help the understanding of respiratory-failure illnesses such as sudden infant
death syndrome, also known as cot death, and a potentially fatal syndrome called Ondine's curse. If problems in glial-cell
function can be shown to cause these conditions, astrocytes could perhaps be targeted in the future development of therapies.

"What this study does is beautiful and very exciting," says Philip Haydon, a neuroscientist from Tufts University School of
Medicine in Boston, Massachusetts. "The next step would be to selectively block astrocytic calcium signals or the release
of ATP, then drive the pH change and see what happens — that would determine whether astrocytes are absolutely necessary in
controlling breathing."

Gourine agrees that it is important to develop tools to inhibit such astrocyte responses, but says it is a "major challenge".

Brian MacVicar, a cellular neuroscientist from the University of British Columbia in Vancouver, Canada, says that there has
been some disagreement about the interaction between astrocytes and neurons. The question is whether astrocytes can really
do anything rapidly enough to alter ongoing behaviour by influencing neuron activity, he says, or if they have a more passive
role.

"The astrocytes are shown here to respond rapidly — within seconds — to a physiological stimulus," he says. "The impact of
this paper will convince the most hardened sceptic that astrocytes can change neuronal activity in response to a stimulus
and thereby alter a behavioural response."

But some researchers say that caution is needed in interpreting data from such animal studies. "Everybody can probably agree
that astrocytes can signal to neurons in cell culture," says Attwell. "But the problem is that when you want to move that
into living organisms, it is more complicated to interpret the data, and especially to determine exactly what the signalling
mechanism is."